Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

Mohd Fadhlizil Fasihi Mohd Aluwi, Kamal Rullah, Andreas Koeberle, Oliver Werz, Nur Sakinah Abdul Razak, Leong Sze Wei, Fatimah Salim, Nor Hadiani Ismail, Ibrahim Jantan, Kok Wai Lam

Research output: Contribution to journalArticle

Abstract

The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors.

Original languageEnglish
Pages (from-to)844-850
Number of pages7
JournalJournal of Molecular Structure
Volume1196
DOIs
Publication statusPublished - 15 Nov 2019

Fingerprint

Curcumin
Macrophages
Biosynthesis
Interleukin-1
Dinoprostone
Esters
Anti-Inflammatory Agents
Derivatives
Pharmaceutical Preparations
pyrazole
Lead
prenyl

Keywords

  • 3D-QSAR CoMFA
  • mPGES-1
  • PAINS
  • PGE

ASJC Scopus subject areas

  • Analytical Chemistry
  • Spectroscopy
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Fasihi Mohd Aluwi, M. F., Rullah, K., Koeberle, A., Werz, O., Abdul Razak, N. S., Wei, L. S., ... Lam, K. W. (2019). Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. Journal of Molecular Structure, 1196, 844-850. https://doi.org/10.1016/j.molstruc.2019.07.004

Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. / Fasihi Mohd Aluwi, Mohd Fadhlizil; Rullah, Kamal; Koeberle, Andreas; Werz, Oliver; Abdul Razak, Nur Sakinah; Wei, Leong Sze; Salim, Fatimah; Ismail, Nor Hadiani; Jantan, Ibrahim; Lam, Kok Wai.

In: Journal of Molecular Structure, Vol. 1196, 15.11.2019, p. 844-850.

Research output: Contribution to journalArticle

Fasihi Mohd Aluwi, MF, Rullah, K, Koeberle, A, Werz, O, Abdul Razak, NS, Wei, LS, Salim, F, Ismail, NH, Jantan, I & Lam, KW 2019, 'Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA', Journal of Molecular Structure, vol. 1196, pp. 844-850. https://doi.org/10.1016/j.molstruc.2019.07.004
Fasihi Mohd Aluwi MF, Rullah K, Koeberle A, Werz O, Abdul Razak NS, Wei LS et al. Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. Journal of Molecular Structure. 2019 Nov 15;1196:844-850. https://doi.org/10.1016/j.molstruc.2019.07.004
Fasihi Mohd Aluwi, Mohd Fadhlizil ; Rullah, Kamal ; Koeberle, Andreas ; Werz, Oliver ; Abdul Razak, Nur Sakinah ; Wei, Leong Sze ; Salim, Fatimah ; Ismail, Nor Hadiani ; Jantan, Ibrahim ; Lam, Kok Wai. / Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. In: Journal of Molecular Structure. 2019 ; Vol. 1196. pp. 844-850.
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